PROJECT SUMMARY/ABSTRACT Despite the availability of effective antiretroviral therapies, cognitive deficits remain prevalent in HIV-infected (HIV+) individuals. HIV+ women show prominent deficits in verbal learning and memory, and stress is a major contributor to these deficits. In fact, we have shown that stress has more profound effects on verbal memory in HIV+ women than in HIV-uninfected (HIV-) women. Our structural and functional neuroimaging findings link these stress-related memory impairments in HIV+ women to prefrontal cortical atrophy and decreased prefrontal cortex (PFC) functioning. Cortisol, a glucocorticoid that is released following a stressor and which is elevated with chronic stress, is known to influence both hippocampal and PFC function. Clinically, this is relevant because LDH can be administered exogenously and safely in the form of low-dose hydrocortisone (LDH). In healthy individuals, LDH impairs cognition, but in individuals with post-traumatic stress disorder (PTSD) LDH enhances cognition. We recently extended this line of LDH research to HIV in a pilot study of a single dose of LDH (10mg) in HIV+ women with high levels of perceived stress but no current psychiatric comorbidities. Notably, verbal learning and memory improved 4 hours following treatment with LDH compared to placebo. Although the mechanisms contributing to this effect are unknown, LDH normalizes stress-induced alterations in the hypothalamic-pituitary-adrenal (HPA) axis and inflammation. Here we propose to examine the robustness and clinical significance of these findings in a larger sample of HIV+ women demonstrating cognitive dysfunction and reporting high levels of stress, trauma history, and mental health risk factors. Women meeting enrollment criteria will complete three cognitive assessments. The first and second assessments will be embedded in a double- blind, placebo-controlled, cross-over study of a single administration of LDH (10 mg in pill form) versus placebo (targeted n=100). The within-subject design controls for common cofounds (e.g., psychological risk factors, substance use history) that could complicate interpretation of LDH effects in a population of HIV+ women. We will measure cognitive performance 30 minutes and 4 hours post-dosing, because an emerging literature shows that the cognitive effects of LDH depends on timing of the assessment post-dosing. The 30-minute assessment addresses how the maximal cortisol levels following LDH affect cognition. This immediate assessment is standard in studies of stress and cognition and allows for comparisons with the broader literature. More novel and clinically important is the 4-hour assessment which occurs post-peak, when cortisol levels are more steady state and typical of the broader daily cortisol profile following LDH. The third assessment will take place after 4 weeks of treatment with LDH or placebo. That assessment addresses the clinical significance and safety of longer-term LDH treatment. Lastly, we will explore glucocorticoids and inflammation and immune activation as mechanisms by which LDH might affect cognition. [This novel study will be the first to target mental health related mechanisms (e.g., HPA axis dysregulation) to enhance cognition in HIV+ women. If in 5-years this study verifies and extends our initial findings that LDH enhances cognition in HIV+ women then we will have identified a novel therapeutic target for further clinical and mechanistic investigations.]